HERSCHEL K. MITCHELLAND JOSEPH F. NYC
674
This residue was distilled under reduced pressure to give 94.6 g. (30.9'70) of acetopropyl alcohol and 12.2 g. (3.9%) of 1,4-pentanediol. The acetopropyl alcohol had the ~ properties: b. p. 75" (3 mm.); ds4 0.993; n Z 51.4350. 4,s -Dihy dro -2 -methylf wan .-This dihydromethylfuran was prepared from acetopropyl alcohol by the method of Kyrides and Zienty.lo Acetopropyl alcohol (25 g.) was heated to boiling at atmospheric pressure in a flask equipped with a 14" X 3/4" helices-packed column. Distillate temperature did not exceed 72". Near the end of the distillation heat was applied to the column to prevent excessive holdup. The distillate consisting of water and dihydromethylfuran was transferred to a separatory funnel and the water layer removed. The dihydromethylfuran (19 g., 92.3%) contained a trace of water. After standing for twelve hours this water had reactedo; redistillation gave pure dihydromethylfuran (b. p. 80 , 11% 1.4290, dz64 0.895) and a trace of acetopropyl alcohol. This method was used by Kyrides and ZientylO to separate acetoprepyl alcohol from l ,-l-pentanediol. The dihydromethylfuran is readily converted back to acetopropyl alcohol by reaction with water catalyzed by a trace of acid.
2-Methoxy-Z-methyl-tetrahydrofuran.-4,5-Dihydro-2methylfuran (10 9.) was dissolved in 10 cc. of methyl alcohol containing two drops of acetic acid. The temperature of the solution rose to 39" and remained there for fifteen minutes. The reaction mixture was then refluxed on a steam-bath for an additional fifteen minutes after which the acid was neutralized by addition of an excess of sodium methoxide. 'The undissolved solid was removed by filtration and the filtrate distilled. 2-Methoxy-2-methyltetrahydrofuran, having a menJhol-like odor, was obtained in 88.6% yield: b. p . 114.5 ; T Z ~ D 1.4110; d'J64 0.932. Anal. Calcd. for CBH1202: C, 62.07; H , 10.34; OCH3, 26.72. Found: C , 61.96; H , 10.36; OCH3, 25.90. Reasouing by analogy with the hydrolysis product from
[CONTRIBUTED
FROM
Vol. GO
4,5-dihydro-Z-methylfuranthe alcoholysis product may have either an open-chain or cyclic structure illustrated by formulas I and I 1
I
I1
Molar refractivity of the compound obtained indicates the cyclic form ( 1 1 ) . Anal. MD found, 30.90. J I D calcd. for I, 32.61; for 11, 30.99. Treatment of 10 g. of 2-methoxy-2-methyl-tetrahydrofuran with 10 cc. of water effected a rapid hydrolysis to give methanol and acetopropyl alcohol (6.5 g.).
Summary Methylfuran has been converted to 1,4-pentanediol in 50-60% yields by hydrogenation in the presence of water and a trace of acid. Acetopropyl alcohol was prepared in 25-35~0 yield by interrupting the reaction after absorption of 1 mole of hydrogen/mole of methylfuran. The reversible conversion of acetopropyl alcohol to 4,5-dihydro-2-methylfuran confirms a previously proposed mechanism by which %methylfuran is converted to acetopropyl alcohol. 2-Methoxy-2-methyl-tetrahydrofuran,a new compound having a menthol-like odor, has been prepared by methalcoholysis of 1,3-dihydro-2methylfuran. PEORIA 5, ILL.
KERCKHOFF LABORATORIES OF BIOLOGY, CALIFORNIA
RECEIVED SEPTEMBER 30, 1946
INSTITUTE OF
TECHNOLOGY ]
Intermediates in the Synthesis of Orotic Acid from Oxalacetic Ester and Urea BY HERSCHELK. MITCHELLAND JOSEPH F. NYC Muller in 1897l reported the synthesis of a com- found that this substance was not identical with pound, through condensation of oxalacetic ester orotic acid. The, ester prepared by Muller' was and urea, to which he assigned a structure corre- then re-examined by WheelerP4who considered sponding to an ester of 4-car6oxy-uracil. This that the synthesis might result in either a pyrimisubstance received little attention until after the dinecarboxylic acid (I) or a substituted hydantoin isolation from milk, by Biscaro and Belloni,2 of a (11) in accordance with the reactions nitrogenous heterocyH V H I clic acid (orotic acid). 2" COOCsHS N N HCI o=c/ \c=O KOH o=c/ \c=O Although these investiI I gators assigned a seven- O=C ICHz I I w I I membered ring strucNHz I O=C I AcH HN\CNCH HN\&CH ture t o the acid, i t was I I pointed out by Wheeler, COOCzH6 COOCzHs COOH Johnson and Johns3 VI H 11 that the ernpiricalformKOH o=c(=F=O o=c(+ ula was identical with N--C=CH-COOCzHa N--C=CH COOH that of a carboxyl deH H rivative of uracil. The latter workers synthesized 5carboxyuracil and The acid oBtained was identified as 4-carboxyuracil by conversion t o 5,5'-dibromo-barbituric (1) R. Muller, J . prakf. Chcm., 66, 480 (1897). (2) G. Biscaro and E. Belloni, Ann. Sac. Chim. Milono, XI, fasc acid (111) with bromine water. On treatment I and I1 (1905); Chcm. Zcntr., [II] 68, 64 (1905). with bromine water 5-(carboxy-methylidene)(3) R. L. Wheeler, T. B. Johnson and C. 0. Johns,A m . Chsm. J , , __f
k1
87, 392 (1907).
-
(4) H.
L. Wheeler, ibid., 88, 868 (1907).
March, 1947 INTERMEDIATES IN SmTIiEsIs OF OROTIC ACIDFROM OXALACETIC ESTERAND UREA 675 H
/I
0
hydantoin (11) gives rise to the hydantoic acid (IV) .K As a result of this work, that of Johnson and CaldwelP and of Bachstez' it was established that orotic acid is identical with 4-carboxyuracil (I). Conclusions Sroni investigations carried out in this Laboratory are in accord with the accepted structure for orotic acid but they are not in agreement with the structure V accepted by Wheeler4 and by Bachstez' for the ester prepared by Muller' from oxalacetic ester and urea. We have demonstrated that this ester has the structure VI and that the synthesis of orotic acid proceeds according to the following series of reactions /NHz
COOCZH,
o=c \ N H ~ + o=cI
H C1
-+
I CH2 1
AcH
is dependent on hydrolysis of the compound to give the acid (I). His procedure calls for the evaporation to a small volume of a solution of the ester in aqueous alcoholic potassium hydroxide, and if this evaporation is carried out a t loo', orotic acid is indeed obtained. However, if the evaporation is carried out a t 50' the hydantoin I1 is the major product. This hydantoin is in turn converted to orotic acid by heating with aqueous alkali a t 100'. The two acids have the same empirical formula but differ markedly in acidic strength, decomposition temperature, reactivity toward bromine water, and absorption spectrum in ultraviolet light. The structures of the ester (VI) and the acid (11), both obtained from the reaction of oxalacetic acid and urea, have been established through the reactions shown. The hydantoin (VII) was synthesized by Grimeaus and by Gabriel5from asparagin and aspartic acid, respectively. The latter investigator synthesized I1 from VII. I n addition Gabriel prepared the hydantoic acid (IV) from the acid (11) and from 5-methyl-hydantoln (VI111 H IT-c=o o=c( I 'N-C-CH~ H H
COOCzHs
0-c
c=o
N-
(X-C H
I
KOH
/I CH i
__f
50 O
COOCzH, VI H N-C==O
o=c'
'N-c
1
KOH
T z
I
I
!H
I
COOH
COOH I1
I Proof by Wheeler of the structure of the ester (V) H
N-C=O
2KOH
VI11
thus establishing the hydantoin structure of 11. Additional evidence for this structure comes from the work of Grimeau,8 who synthesized a compound believed to be the amide of VI1 directly from asparagin and urea. Since asparagin is an amino acid the amide obtained is most probably a hydantoin derivative rather than a pyrimidine derivative. These compounds prepared by Grimeau8 and by Gabriel5 have been synthesized in this Laboratory according to their methods and compared with the products of the reaction of oxalacetic acid and urea. H
P;-c=o
ExDerimental
5-( Carbethoxymethylidene) -hyo=c I dantoin (VI) .-This compound was _____) O="
